tbuckley/cabot-search huggingface dataset:
Phase II basket trial evaluating the efficacy of pembrolizumab (PE) combined with vorinostat (VO) in patients (pts) with recurrent and/or metastatic squamous cell carcinoma (SCC).
Authors: Christophe Le Tourneau, Frédéric Bigot, Damien Vansteene, Maud Kamal, François Ghiringhelli, Luca Mazzarella, Christian Borel, Raphael Chaltiel, Benoit You, Carlos A. Gomez-Roca, Sophie Cousin, Elodie Coquan, Aurélien Lambert, Esma Saada-Bouzid, Xavier Durando, François Legrand, Amellie Lusque, Fabrice Andre, Thomas Filleron
Journal: Journal of Clinical Oncology (2023)

2597 Background: Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. Patients and Methods: PEVOsq is an open-label, non-randomized, multi-center, basket phase II trial, evaluating the efficacy of pembrolizumab in combination with vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma of the cervix, head and neck, anus, vulva/vagina, penis, and lung. Patients had to be PD1/PD-L1 antagonist-naïve. There was no selection based on PD-L1 expression nor on HPV status, and no restriction in terms of prior lines of treatments. Pembrolizumab dose was 200 mg Q3W IV, and vorinostat 400 mg QD PO. Sample size was determined for each cohort using an A’Hern design. Primary endpoint was objective response rate (ORR) according to RECISTv1.1. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Results: Among 112 included patients, 111 were evaluable for safety and 107 for efficacy. The lung cohort was closed prematurely because of lack of enrollment. Median age was 61 years old [range: 18-85] and the median number of prior lines of therapies was 1 [range: 0-4]. ORR, PFS, G3/4 treatment related adverse events (TRAE), and OS are reported. 28 patients (26%) had an objective response and median DOR was 9.7 months [95%CI: 3.1-15.2]. Results per PD-L1 status will be presented at the meeting. Pembrolizumab and vorinostat were stopped for toxicity in 9% and 39% of patients, respectively. 60% of patients had a dose-reduced of vorinostat for toxicity. Pembrolizumab safety was as expected. Main vorinostat toxicities included hematological toxicity, gastrointestinal disorders, and asthenia and creatinine increase. Conclusions: Pembrolizumab combined with vorinostat showed encouraging antitumor activity in squamous cell carcinoma with unselected PD1/PD-L1 status, especially in cervical and anal cancer, although vorinostat dose had to be reduced because of toxicity in a substantial proportion of patients. Clinical trial information: NCT04357873 . [Table: see text]
A powerful drug combination strategy targeting BRAF-mutant melanoma.
Authors: Luke Daniel Rothermel, Mehrdad Zarei, Alexander W Loftus, Jonathan J. Hue, Omid Hajihassani, Hallie J Graor, Jordan Michael Winter
Journal: Journal of Clinical Oncology (2023)

3152 Background: BRAF inhibitors, such as vemurafenib and dabrafenib, are effective in treating patients with melanoma harboring (V600E) BRAF mutations. These drugs block the activity of the mutated BRAF protein, which impacts the development and progression of melanoma. Despite initial efficacy, drug resistance reliably occurs leading to disease relapse. Here we show how BRAF inhibitors cause metabolic reprogramming in melanoma cells to achieve drug resistance and promote cell survival. Previously we demonstrated that wild-type isocitrate dehydrogenase 1 (wtIDH1) supports mitochondrial function and maintains redox homeostasis in melanoma, and that an FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtIDH1 inhibitor. Thus, we hypothesized that wtIDH1 inhibition would synergize with BRAF inhibition. Methods: Metabolomic profiling using LC-MS determined the impact of BRAF inhibition on cellular metabolism. Cell viability was assessed by PicoGreen in drug combination assays. Synergism was calculated using the Bliss-Independence dose-response model for drug interaction. In vivo modeling of AG-120 in combination with BRAF inhibition used melanoma cell xenografts in athymic nude mice for tumor volume analyses, and survival studies were performed in both immunocompetent C57BL/6J mice (murine YUMM1.7 cells) and immunocompromised athymic nude mice (human A375 cells). Results: Metabolomics data suggest that BRAF-mutated melanoma cells treated with BRAF inhibitors increased oxidative metabolism and mitochondrial dependence (i.e., survival adaptations). These alterations suggest an opportunity for mitochondrial inhibitors to improve drug efficacy. Targeting wtIDH1 with AG-120 in combination with dabrafenib significantly reduced melanoma cell viability. A positive synergy score and Bliss score greater than 1 indicate that the combined treatment was more effective in reducing cell viability than either treatment alone. Further, the combination of AG-120 and dabrafenib was the most effective in vivo, reducing tumor growth in the BRAF-mutated melanoma xenograft model, and improving mouse survival compared to monotherapy controls. Mice tolerated combination therapy with no reduction in body weight observed. Conclusions: Our findings indicate that dual inhibition of mutated BRAF and wild-type IDH1 represents a novel treatment strategy for BRAF-mutated melanomas, with potential for application to other BRAF-mutated cancers (e.g., colon, hepatobiliary, thyroid, etc.).
Health-related quality of life (HRQoL) in the phase 3 KEYNOTE-966 study of pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) versus placebo plus gem/cis for advanced biliary tract cancer (BTC).
Authors: Changhoon Yoo, Richard S. Finn, Heinz-Josef Klümpen, Robin Kate Kelley, Arndt Vogel, Junji Furuse, Zhenggang Ren, Thomas Yau, Stephen Lam Chan, Masato Ozaka, Sang Cheul Oh, Shanzhi Gu, Joon Oh Park, Juan W. Valle, Julien Edeline, Shital Kamble, Josephine M Norquist, Li Yu, Usha Malhotra, Makoto Ueno
Journal: Journal of Clinical Oncology (2023)

4003 Background: In the randomized, double-blind, phase 3 KEYNOTE-966 trial (N = 1069; NCT04003636), pembro + gem/cis significantly improved OS versus placebo + gem/cis (HR 0.83; 95% CI 0.72-0.95; P = 0.0034) and had an expected and manageable safety profile as first-line therapy for unresectable locally advanced or metastatic BTC. We present the protocol-specified exploratory patient-reported outcomes (PROs) from KEYNOTE-966. Methods: PROs were assessed using the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L questionnaires. The analysis population included all treated patients (pts) who completed ≥1 HRQoL assessment for the specific endpoint. A constrained longitudinal analysis model (covariates: treatment, time, treatment by time interaction, and stratification factors) was used to compare least squares mean (LSM) score changes from baseline (BL) to wk 18 (ie, latest timepoint that completion was ≥60% and compliance was ≥80%) in QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and role functioning (RF), QLQ-BIL21 jaundice and pain, and EQ-5D-5L visual analogue scale (VAS). A stratified Cox proportional hazards model was used to assess the magnitude of the between-arm difference in time to deterioration (TTD) in GHS/QoL, PF, RF, jaundice, and pain (ie, time to first onset of ≥10-point deterioration from BL in each scale/subscale confirmed by ≥10-point deterioration from BL at the next visit; established as clinically relevant). Results: Questionnaire compliance was &gt;87% from BL to wk 18 in both arms. LSM changes from BL to wk 18 in QLQ-C30 GHS/QoL, PF, and RF, QLQ-BIL21 jaundice and pain, and EQ-5D-5L VAS were similar between arms. Time to deterioration was also similar between arms: median not reached (NR) vs 21.2 mo for GHS/QoL (HR 0.86, 95% CI 0.70-1.07), NR vs 12.0 mo for PF (HR 0.95, 95% CI 0.78-1.17), 6.5 mo vs 5.8 mo for RF (HR 0.98, 95% CI 0.81-1.18), NR vs NR for jaundice (HR 1.20, 95% CI 0.94-1.54), and NR vs NR for pain (HR 0.79, 95% CI 0.59-1.05). Conclusions: HRQoL was maintained when pembro was added to gem/cis. Together with the efficacy and safety data, these results support pembro + gem/cis as a new first-line treatment option for advanced BTC. Clinical trial information: NCT04003636 . [Table: see text]
Immune-mediated adverse event management at a tertiary care cancer center.
Authors: Malek Shatila, Farzin Eshaghi, Austin Thomas, Andrew Kuang, Ala Abudayyeh, Ajay Sheshadri, Nicolas Palaskas, Anusha Thomas, Hao Chi Zhang, Yinghong Wang
Journal: Journal of Clinical Oncology (2023)

e14697 Background: Our understanding of immune-related adverse events (irAEs) has evolved rapidly with management guidelines constantly being updated. We aim to explore temporal changes in irAE management at a tertiary cancer care center to identify areas for potential improvement. Methods: This was a single-center, retrospective study including patients who developed a GI, pulmonary, renal, or cardiac irAE between 07/01/2019-10/01/2019 compared to a contemporary cohort from 2021. The follow-up window was for up to a year after diagnosis. Data collected included patient demographics and irAE management and outcomes. Results: Endoscopic evaluation and GI follow-up after discharge for patients with GI irAEs fell over the years. Despite this, there was a decline in symptom duration and steroid taper attempts. The pulmonary service showed improvements in consultation, hospital admission and re-admission, and ICU admission. However, follow up post-hospital discharge were consistently low ( &lt; 50%). Rate of cardiology consultation was consistently high across the years with an equally fast time to consultation, and myocarditis cohort in 2021 had a higher clinical response rate than the 2019 cohort. There were no major differences across the years for renal irAEs. We found that outpatient treatment and earlier GI consult improved outcomes in GI irAEs. For pulmonary irAEs, hospitalization, symptom recurrence, multiple steroid tapering courses, and hospital readmission were associated with less pneumonitis remission. Conclusions: This is one of the few qualitative studies exploring current practice in managing irAEs. We identified areas to improve the management on across all specialties, and found specific factors associated with better outcomes in GI and pulmonary irAEs. Together, these findings can help improve the quality of irAE management algorithms at our institution. [Table: see text]
The clinical impact of soluble natural killer cell group 2-member D (NKG2D) receptor ligands on tumor tumorigenicity and anti-tumor immunity.
Authors: Anthony V. Serritella, Pablo Saenz-Lopez, Payal Dhar, Sizhe Liu, Jennifer Wu
Journal: Journal of Clinical Oncology (2023)

e14557 Background: NKG2D is an activating receptor expressed on all human natural killer (NK) cells and CD8 T-cells. It is widely accepted that human tumors shed soluble NKG2D ligands, such as soluble major histocompatibility complex-I chain-related molecule (sMIC), to evade immune activation. Harnessing the NKG2D/NKG2D-ligand axis has emerged as a promising avenue for immunotherapy. However, controversy exists over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory. Methods: Cell lines for melanoma (B16F10), Lewis lung carcinoma (LLC1), and prostate cancer (TRAMP-C2, T-C2) were used as parental cell lines in this study. Derivative cell lines over-expressing the soluble human NKG2D ligand sMICB (B16F10-sMICB, TC2-sMICB and LLC-sMICB) were created. We inoculated these 3 syngeneic transplantable tumor models and their respective parental lines into mice and compared tumor incidence/growth over time. We also compared surface markers representative of cell stemness (SCA-1, CD166 and CD133) in mouse cancer cells between the sMICB-expressing tumor cells and their respective parental cell lines. We then characterized the tumor immune microenvironment by flow cytometry. Results: B16F10-sMICB mice demonstrated a significant delay in tumor development compared to control mice (23 vs. 6 days, p &lt; 0.05). Over longer follow-up, rapid tumorigenesis still occurred in the experimental group, with a 50% tumor incidence by day 26. By contrast, the TRAMP-C2-sMICB mice demonstrated higher tumorigenic ability (p &lt; 0.05). LLC-sMICB mice demonstrated no difference in tumorigenicity. Time to tumor onset was more strongly associated with expression of stemness-like markers rather than sMIC. Once tumors were established, they grew significantly more aggressively in the TRAMP-C2-sMICB, LLC-sMICB and B16F10-sMICB lines vs. their parental counterparts. sMICB expressing tumors contained significantly lower percentages of NK cells and CD8 T-cells in tumor infiltrates than their respective parental lines. NK cells and CD8 T Cells from sMICB-expressing tumors had an impaired capacity to produce interferon gamma. Conclusions: Expression of a soluble NKG2D ligand had minimal impact on tumor establishment but facilitated more aggressive growth of established tumors due to immune suppression. Soluble NKG2D ligands imprint negative anti-tumor immunity onto established tumors. Our data differentiated the impact of NKG2D ligands on tumor onset vs. tumor progression and reinforced the translational concept that soluble NKG2D ligands are strong therapeutic targets for future study.
Phase I results of human endogenous retrovirus type-E (HERV-E) TCR transduced T-cells in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Rosa Nadal, Stefan Barisic, Gina M. Scurti, Elena Cherkasova, Long Chen, Kristen Wood, Steven L. Highfill, Brian Wells, Georg Aue, Reem Shalabi, Thomas E. Hughes, Xin Tian, Yifei Xu, Ashkan A. Malayeri, Mohammadhadi H. Bagheri, Robert N. Reger, Michael I. Nishimura, Richard W. Childs
Journal: Journal of Clinical Oncology (2023)

2549 Background: The CT-RCC HERV-E is expressed in the majority of ccRCC tumors with no expression in normal tissues. T-cells transduced to express a HERV-E TCR are cytotoxic to ccRCC &amp; mediate tumor regression of human ccRCC in a murine model. We developed a method to manufacture HERV-E TCR transduced T-cells (HERV-E TCR) for clinical development. Methods: We conducted a phase I dose-escalation trial (DL1:1x10 6 , DL2:5x10 6 , DL3:1x10 7 &amp; DL4:5x10 7 cells/kg) to evaluate the safety of adoptively infused HERV-E TCR in mccRCC pts. HERV-E TCR contain T-cells engineered to express an HLA-A*11 restricted HERV-E TCR and a truncated CD34 cassette for in vivo monitoring. Eligible HLA-A*11 pts had mccRCC, ECOG 0-1 &amp; prior antiangiogenic &amp; checkpoint inhibitors therapy unless contraindicated/unavailable. Cyclophosphamide &amp; fludarabine were given followed by HERV-E TCR infusion &amp; IL-2 administration. Results: 14 HLA-A*11+ pts (median age 56) were treated including 3 pts in each DLs 1-3 &amp; 5 pts in DL4. 86% had ≥ 3 prior treatment lines (range 1-7): 36% had high-dose IL2, 57% Ipilimumab-Nivolumab &amp; 50% ≥ 3 lines of anti-VEGFR therapy. Bone, liver &amp; brain metastases were present in 71%, 43%, and 14% of pts. All HERV-E TCR products met sterility, purity, and potency criteria for release and infusion (Table). No HERV-E TCR dose-limiting toxicities or treatment-related deaths occurred. Pts received a mean: 12 IL-2 doses (IQR 11-14). 57% pts had G3-4 febrile neutropenia &amp; 7% G3-4 capillary leak syndrome. 1 pt experienced G2 skin rash possibly related to HERV-E TCR. Best response included 7% pts with partial response &amp; 29% with stable disease ≥ 8 weeks. The mPFS: 62 days (IQR 31,90). At DL4, TCR transgene expression was detectable in PBMCs at a mean 6.3% (range (r) 0.02-25), 12.3% (r 0.01-61.2), 3.45% (r 0.00-13.7) &amp; 2.89% (r 0.00-11.5) on days 4, 7, 14, &amp; 21. HERV-E TCR were detected in the malignant pleural effusion of 1 pt. Conclusions: This is the first trial evaluating TCR-engineered T-cells targeting a human endogenous retrovirus in ccRCC. The manufacturing method utilized produced large numbers of highly purified CD8+ HERV-E reactive T-cells that were not associated with any dose limiting toxicities when given at doses up to 5x10 7 cells/kg. For pts in DL4, HERV-E TCR were observed to proliferate in vivo, traffic to a metastatic site, and induce tumor regression in one mccRCC pts. Clinical trial information: NCT03354390 . [Table: see text]
Discontinuation of immunotherapy over 2 years for patients with non–small cell lung cancer (NSCLC): A search for predictors.
Authors: Priscilla Cascetta, Anna Reni, Francesco Facchinetti, May-Lucie Meyer, Mariona Riudavetz, Mihaela Aldea, Filippo Gustavo Dall'Olio, Arianna Marinello, Marco Tagliamento, Jordi Remon Masip, Benjamin Besse, David Planchard, Fabrice Barlesi, Lisa Derosa
Journal: Journal of Clinical Oncology (2023)

2661 Background: In advanced NSCLC, treatment completion at 24 months emerged in trials evaluating immune checkpoint inhibitors (ICI). Nevertheless, in clinical practice the question of the optimal treatment duration is under debate. Methods: We performed a retrospective study on advanced NSCLC treated with ICI (alone or with chemotherapy) at Gustave Roussy before 2021. Among patients still receiving ICI at 12 months, we analyzed the reasons for ICI discontinuation at 18 and 24 months. Results: Of the 682 patients treated with ICI (first-line for n=230, 33.7%), 159 (23.3%) received ICI for ≥ 12 months and 122 (17.9%) for ≥ 18 months. Between 18-24 months, 20 (57.1%) patients interrupted ICI for progressive disease (PD), 8 (22.8%) for toxicity and 7 (20.0%) after discussion with the patient. Out of the 88 (12.9%) patients who completed 2-years of ICI (median duration of treatment: 31.46 months, first-line for n=51), 22 (25.0%) patients discontinued ICI for PD and 40 (45.5%) without PD: 14 (15.9%) for toxicities, patient request or unknown causes and 26 (29.5%) for clinical decision before (n=16, 61.5%) or after (n=10, 38.5%) 30 months of treatment. Discontinuation according to phase III clinical trial design was supported by complete response (CR) by PET imaging +/- tissue biopsy of metabolically active lesions +/- ctDNA in 17 (65.4%) cases just before therapy discontinuation. After a median follow-up of 45.6 months since treatment discontinuation for these 26 patients, only two experienced PD at 4 and 6 months from ICI interruption, in both cases with no proof of CR at ICI discontinuation (p=0.111). The remaining 26 (29.5%) patients who continued ICI after 2 years, are on treatment based either on absence of CR at PET-CT +/- tissue biopsy of metabolically active lesions (n=20, 76.9%) or after discussion with the patients (n=6, 23.1%). After a median follow-up of 40.17 months from the of 24-months landmark, the median progression-free survival was unreached in both continuation and discontinuation groups. Conclusions: The patients who completed 2-years of ICI treatment usually continue to experience long‐term response after discontinuation. Considering that a subgroup of patients could still benefit from maintained ICI administration, PET imaging was considered to guide ICI cessation or continuation. Prospective studies specifically designed to investigate biomarkers of maintained responses or residual disease (imaging, ctDNA, multi-omics including microbiome) are required to establish the indication for ICI continuation or stop for each patient.
LANTana trial protocol: An open label, single arm, phase Ib study to evaluate the effect of pre-treatment with ASTX727 (a demethylating agent) followed by lutetium Lu 177 dotatate in patients with progressive, metastatic neuroendocrine neoplasias (NENs).
Authors: Rohini Sharma, Caroline Ward, Mitesh Naik, Saraih Khan, Tara Barwick, Maria Martinez, Hooshang Izadi, Eric O. Aboagye
Journal: Journal of Clinical Oncology (2023)

TPS4192 Background: Neuroendocrine neoplasias (NENs) are characterised by the presence of somatostatin receptors (SSTR) on cell surface, in particular SSTR2. Somatostatin and its stable analogue (SSA) bind with high affinity to SSTR2. SSA can be radiolabelled, to both stage NENs using positron emission tomography (PET), and to deliver selective radiotherapy; peptide receptor radionuclide therapy (PRRT). PRRT consists of SSA linked to the long acting radionuclide. Radiolabelled SSA binds to SSTR2 and the complex is internalised delivering high dose radiation directly to the cancer. PRRT has been significantly improve survival outcomes and maintain quality of life in metastatic disease. Suitability for PRRT depends on presence of SSTR2 as determined by PET imaging, commonly with [ 68 Ga]-dotatate-PET. 20% of patients will have low or no uptake on [ 68 Ga]-dotatate-PET precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. We have shown that the use of the demethylating agent, guadecitabine, increases uptake on PET imaging in such that tumours previously negative on PET imaging, become positive, correlating with a dose dependent increase in tumoural SSTR2 expression. Combination guadecitabine and PRRT was well tolerated in vivo models of NETs. Overall aim was to utilise [ 68 Ga]-dotatate-PET as a biomarker of SSTR2 re-expression following treatment with the demethylating agent, ASTX727, such that patients previously unsuitable for PRRT can receive therapy, improving clinical outcome. 1) Utilise [ 68 Ga]-dotatate-PET to image epigenetic regulation of SSTR2 in response to ASTX727. 2) Evaluate clinical efficacy and safety of ASTX727 pre-treatment in combination with PRRT. 3) Explore impact on quality of life of combination therapy. Methods: 27 patients with no or equivocal uptake on [ 68 Ga]-dotatate-PET will be enrolled. [ 68 Ga]-dotatate-PET will be performed at baseline and after 8days of ASTX727 (oral, fixed dose 100mg cedazuridine + 35mg decitabine). If there is a significant increase in PET uptake, patients will receive combination ASTX727 and PRRT (Lutathera). Treatment will be repeated every 2months for 4 cycles. Response assessment (RECIST 1.1), tolerability and QoL will be assessed at start of each cycle. Tumour biopsies will be taken at baseline, and after cycle1 of ASTX727 (n=5), for SSTR2 methylation. Methylation will be correlated with PET uptake and outcome. LINE-1 methylation in peripheral blood monocytes will be assessed throughout. Current enrolment: 4. Clinical trial information: NCT05178693 .